KR930007949A - Substituted pyrimidines, methods for their preparation, pharmaceutical compositions containing them and uses thereof - Google Patents

Abstract

This invention relates to pyrrolo-, pyrido-, azepino-, and azocinopyrimidines of the general formula I <CHEM> useful for treating hypertension or congestive heart failure and for preventing or treating restenosis following angioplasty, to pharmaceutical compositions, and to methods for production thereof.

Description

Substituted pyrimidines, methods for their preparation, pharmaceutical compositions containing them and uses thereof

Since this is an open matter, no full text was included.

Claims (61)

A compound of formula (I), or a pharmaceutically acceptable salt thereof, or N-oxide thereof. Wherein R ¹ to R ⁴ are independently H, lower alkyl of 1 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms; R ⁵ is H or, when n is 1, together with R ³ form a double bond; n is 0 to 1; p is 0 to 2; m is 0 to 3; Ar ¹ is or Wherein W is H, lower alkyl of 1 to 6 carbon atoms, halogen, hydroxy, or lower alkoxy of 1 to 6 carbon atoms; Ar ² is or [Where X is CO ₂ H, CN, or R ⁶ is H, tert-butyl, tri-n-butylstannyl or triphenyl methyl). The compound of formula (II) or a pharmaceutically acceptable salt thereof. Wherein R ¹ to R ⁴ are independently H, lower alkyl of 1 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms; R ⁵ is H or, when n is 1, together with R ³ form a double bond; n is 0 to 1; Ar ¹ is or Ar ² or [Where X is CO ₂ H, CN, or R ⁶ is H, tert-butyl, tri-n-butylstannyl or triphenyl methyl). The compound of claim 1 or 2, wherein X is CO ₂ H, CN or Phosphorus compounds. The compound of formula (III) or a pharmaceutically acceptable salt thereof. Wherein R ¹ to R ⁴ are independently H, methyl, trifluoromethyl; R ⁵ is H or, when n is 1, together with R ³ form a double bond; n is 0 to 1; Ar ¹ is or to be The compound of claim 4, wherein 2, 4-dimethyl-5, 6, 8-trihydro-8-[[2 ′-(1H-tetrazol-5-yl) [1, 1-biphenyl] -4-yl ] Methyl] -7H-pyrido [2, 3-d] pyrimidin-7-one or a pharmaceutically acceptable salt thereof. The compound of claim 4, wherein 2, 4-dimethyl-5, 7-dihydro-7-[[2 ′-(1H-tetrazol-5-yl) [1, 1-biphenyl] -4-yl] methyl ] -6H-pyrrolo [2, 3-d] pyrimidin-6-one or a pharmaceutically acceptable salt thereof. 5, 7-dihydro-2-methyl-7-[[2 '-(1H-tetrazol-5-yl) [1, 1-biphenyl] -4-yl] methyl] -4- (trifluoro Methyl) -6H-pyrrolo [2, 3-d] pyrimidin-6-one or a pharmaceutically acceptable salt thereof. 2-methyl-4-trifluoromethyl-5, 6, 8-trihydro-8-[[2 '-(1H-tetrazol-5-yl) [1, 1-biphenyl] -4-yl] Methyl] -7H-pyrido [2, 3-d] pyrimidin-7-one or a pharmaceutically acceptable salt thereof, 2, 4-dimethyl-5, 6, 8-trihydro-8-[[6- [2- (1H-tetrazol-5-yl) phenyl] -3-pyridinyl] methyl] -7H-pyrido [2, 3-d] pyrimidin-7-one or a pharmaceutically acceptable salt thereof. 2-methyl-4-trifluoromethyl-5, 6, 8-trihydro-8-[[6- [2- (1H-tetrazol-5-yl) phenyl] -3-pyridinyl] methyl]- 7H-pyrido [2, 3-d] pyrimidin-7-one or a pharmaceutically acceptable salt thereof. 2, 4-dimethyl-5, 6, 8-trihydro-8-[[5- [2- (1H-tetrazol-5-yl) phenyl] -2-pyridinyl] methyl] -7H-pyrido [ 2, 3-d] pyrimidin-7-one or a pharmaceutically acceptable salt thereof. 2, 4, 6-trimethyl-5, 6, 8-trihydro-8-[[2 '-(1H-tetrazol-5-yl) [1, 1-biphenyl] -4-yl] methyl]- 7H-pyrido [2, 3-d] pyrimidin-7-one or a pharmaceutically acceptable salt thereof. Or 2, 4-dimethyl-8-[[2 '-(1H-tetrazol-5-yl) [1, 1-biphenyl] -4-yl] methyl] -7H-pyrido [2, 3-d ] Pyrimidin-6-one or a pharmaceutically acceptable salt thereof. (a) condensation of pyrimidine of formula (A) with an amine of formula (A-1), or (b) acyclic compound of formula (B) in the presence of a palladium catalyst. Or arylstanan, or (c) a condensation reaction of a bicyclic compound of general formula (C) with a biaryl compound of general stone (C-1), or (d) Wherein R ⁶ is H, tertiary butyl, tri-n-butylstannyl or triphenylmethyl to remove the protecting group from the compound of formula (I), wherein R ⁶ is hydrogen To obtain a compound or (e) reacting a compound of formula (I) wherein X is -CN with an azide reactant Obtaining a compound of the general formula (I) or (f) forming a salt of the compound of the general formula (I) using an inorganic or organic acid or a base, or (g) A process for preparing a compound of formula (I) according to claim 1, characterized in that it is converted to its N-oxide using a peroxidant. H ₂ N- (CH ₂ ) m-Ar ¹ -Ar ² Z ^1- (CH ₂ ) m-Ar ¹ -Ar ² (c-1) Wherein R ¹ to R ⁴ are independently H, lower alkyl of 1 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms; R ⁵ is H or, when n is 1, together with R ³ form a double bond; n is 0 to 1; p is 0 to 2; m is 0 to 3; Ar ¹ is or Where W is H, lower alkyl of 1 to 6 carbon atoms, halogen, hydroxy, or lower alkoxy of 1 to 6 carbon atoms; Ar ² is or [Where X is CO ₂ H, CN or Wherein R ⁶ is H, tertiary butyl, tri-n-butylstannyl or triphenylmethyl; Z ¹ is a leaving group; Y is a para-bromo or para-iodo group; R ⁷ is a lower alkyl group. a) The compound of formula (1) is reacted with an amine of formula (2) to obtain a compound of formula (3), which is reacted with a compound of formula (3) in the presence of a palladium catalyst. Is reacted with an arylboronic acid, and optionally, when R ⁶ is a tert-butyl group, the protective group is removed by acidic hydrolysis to obtain a compound of formula (I). Method for preparing a compound of. H ₂ N- (CH ₂ ) m-Ar ¹ Y Wherein R ¹ to R ⁴ are independently H, lower alkyl of 1 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms; R ⁵ is H or, when n is 1, together with R ³ form a double bond; n is 0 to 1; p is 0 to 2; m is 0 to 3; Ar ¹ is or Wherein W is H, lower alkyl of 1 to 6 carbon atoms, halogen, hydroxy, or lower alkoxy of 1 to 6 carbon atoms; Ar ² is or [Where X is CO ₂ H, CN or Wherein R ⁶ is H, or tert-butyl; Y is a para-bromo or para-iodo group. 9. The aryl boron of formula (4) according to claim 8, wherein the compound of formula (5) is treated with Mg and trialkyl borate of formula (5-1) in an aprotic solvent, followed by acidic or basic post-treatment. A process for producing the compound of formula (4), characterized by obtaining an acid. In the above formula, Ar ² is or [Where X is (Wherein R ⁶ is H, tert-butyl) and R ⁷ is lower alkyl having 1 to 6 carbon atoms. A pharmaceutical composition comprising a compound according to any one of claims 3 to 6 and a pharmaceutically acceptable carrier. A compound according to any one of claims 3 to 6 for use as a medicament. A compound according to any one of claims 3 to 6 for the treatment of hypertension or congestive heart failure. A compound according to any one of claims 3 to 6 for preventing or treating restenosis after hematopoiesis in mammals. ※ Note: The disclosure is based on the initial application.